Effect of Failure To Respond to Targeted Therapy on Response to Cytotoxic Therapy in Pts Age ≥ 60 with Newly-Diagnosed AML.

An increasing number of studies are emphasizing use of less toxic, often called “targeted”, therapies (TT) in pts age ≥ 60 with untreated AML. A significant proportion of TTs are unlikely to produce even “hematologic improvement”, raising the question whether response to subsequent cytotoxic therapy (CT) is adversely affected in pts who fail to respond to TT. From 11/00–7/06, 25 pts received CT (containing ara-C in 20 cases) as 1^st salvage therapy after failing to respond to a 1^st course of TT (23 pts) or relapsing after brief CRs with such therapy. The TTs were decitabine or 5azacitidine +/− valproic acid 9 pts, PKC412 5 pts, tipifarnib 3 pts, HDAC inhibitors 3 pts, others 3 pts. The median age of the 25 pts was 71 years; 12 of the 24 whose cytogenetic status was determined had a normal karyotype (“diploid”), 7 had chromosome 5 and/or 7 abnormalities (-5/7), and 5 various other poor prognosis abnormalities. The CR rate after CT salvage in the 12 diploid pts was 8/12; their median survival was 44 weeks. Among 114 diploid pts who, from 11/00–7/06, met eligibility criteria for TT studies (WBC < 20,000, performance status < 3) but were given ara-C-containing CT as 1^st therapy CR rate was 68% and median survival 53 weeks. Only 1/12 pts with abnormal karyotypes who received CT as 1^st salvage achieved CR; median survival was 13 weeks. In contrast, in the 161 pts with an abnormal karyotype (50% -5/-7) who were given CT as 1st therapy, CR rate was 37% (p = 0.06) and median survival 19 weeks. Subject to various potential selection biases our conclusions are: (1) in diploid pts failure to respond to TT does not materially affect outcome with CT and (2) failure to respond to TT may identify pts with abnormal cytogenetics who are unlikely to respond to CT; in any event, there is no reason to give such pts CT salvage.